The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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Experience with carbonic anhydrase inhibitors?

Discussion in 'General ME/CFS Discussion' started by anciendaze, Sep 15, 2015.

  1. anciendaze

    anciendaze Senior Member

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    Right from the start, I want to emphasize that I am not recommending treatment or making diagnoses in this post. I am asking for information. People with a number of confusing medical problems end up in the ME/CFS category, and some may have been treated with things that are not in common use. I have been given a number of anticonvulsant drugs on the suspicion that I might have a confusing type of epilepsy without obvious seizures, but I have no experience with the type I'm about to describe.

    This question came to me via a friend who has a solid diagnosis of a rare condition called hypokalemic periodic paralysis (PP). In my limited experience it is rare for ME/CFS patients to have actual paralysis, though there are cases with extreme weakness that may be hard to distinguish from some variants of periodic paralysis. Officially, this is a rare genetic disorder with an incidence of about 1 in 100,000. However, about 1/3 of PP patients do not have any known genetic markers. It is also common for it to appear in young adults who previously had no such illness. This could indicate an infectious origin, or the action of genes which only become active at sexual maturity.

    PP is a channelopathy, with potassium channels most commonly affected. We have considerable reason to suspect disturbances in ion channels and fluid regulation in ME/CFS.

    The FDA recently approved the first drug to treat both hypokalemic and hyperkalemic PP, Keveyis (dichlorphenamide/diclofenamide). This is a sulfonamide which acts as a carbonic anhydraze inhibitor.

    This class of drugs has a long and strange history. Some were synthesized around 1910, but their biological activity was not tested. In the early 1930s work on the first antibiotic, Prontosil, discovered antibacterial action with low human toxicity. Subsequent work showed that the chemical precursor sulfanilamide had better antibacterial activity.

    The medical story of carbonic anhydraze inhibitors mainly concerns use in epilepsy and glaucoma, though idiopathic intracranial hypertension has also been treated with these. Here is a list of some drugs in question: acetazolamide, brinzolamide, dorzolamide, methazolamide, sulthiame/sultiame, topiramate.

    One problem with the new approval is that the recommended treatment now appears to cost $120,000 per year. I suspect insurance will not approve this without evidence from genetic markers, which 1/3 of those diagnosed do not have. Sulthiame/sultiame is similar in biochemical activity, and much cheaper. It has been given to children with an unusual form of epilepsy for years.

    My question is about experience from patients here which might guide research on use of any carbonic anhydraze inhibitors for PP patients, who would not be able to afford the newly introduced drug for PP.
     
  2. anciendaze

    anciendaze Senior Member

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    Latest news from PP patients is that a pharmacy has quoted them a rate for Keveyis which amounts to $96,000 per month for 2 x 50 mg. pills per day. (Some patients need 4.) If this is the cost of a simple chemical like a sulfonamide, I can't imagine what some drugs which are really difficult to synthesize would cost.

    What's wrong with this picture?

    Also learned that my suggestion about sulthiame/sultiame based on structure and mechanism ties in with experience treating episodic ataxia, which has symptoms overlapping PP. Episodic ataxia is also closer to what some people being treated for ME/CFS have described to me. Even with an incidence of 1 in 100,000 we can expect several thousand patients of this type to be found in a country the size of the U.S. Several thousand more would have true PP.

    At present, patients with serious disabling genetic disorders like these are accidentally collected into a single wastebasket category which could be labeled "patients who are hard to treat" instead of ME/CFS. No one has described a plan to separate these patients from cases for whom psychiatric treatment is considered appropriate, nor is there a clear boundary between ME/CFS and several known serious physiological problems. The present attitude appears to be that you find out when patients have a life-threatening condition by screwing around for months or years, and waiting to see if they die. If they do, you remove them from your research cohort on the grounds they never had ME/CFS/SEID.

    What's wrong with that picture?
     
  3. adreno

    adreno PR activist

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    There are natural sources of carbonic anhydrase inhibitors:

     
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  4. anciendaze

    anciendaze Senior Member

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    Thanks adreno. The problem with natural sources is that it is hard to control dosage, and some patients are very sensitive to changes in dose.

    The new drug, dichlorphenamide, is said to be 40 times as powerful as acetazolamide. The same chemicals which increase potassium concentrations in some physiological compartments decrease concentration in others. For example, insulin drives carbohydrate metabolism, moving potassium into cells, and lowering concentrations in serum. An overdose of a CA inhibitor can push the patient past the equilibrium point, and into the opposite problem. Both hypokalemic and hyperkalemic PP exist, so it's not always easy to tell which side a patient is on.

    This is where they get into a problem with the kind of simplistic advice doctors often give. Exercise is generally good, but heavy exercise can produce a setback lasting several days. This intrigues me because it sounds like PEM, though with actual paralysis and other distinctive signs. In the worst cases the patient dies because breathing muscles are paralyzed.

    A patient with complicating factors like diabetes has shown adverse response at measured concentrations about 1000th of the recommended dose of acetazolamide. The general approach in these cases is to dissolve the tablet, or a measured part of a tablet, in liquid. This can then be consumed in small amounts, typically many times a day. If you don't know the concentration of active ingredients in the source material you never know how much is being consumed.

    At the other extreme from the patient described above, we have some who have been on dichlorphenamide in the past, when it was more widely available, and functioned pretty well on twice the current recommended dose. This gives a factor of about 80,000 in known differences between patients.

    I'm still trying to understand how a relatively simple chemical approved and used for common diseases like glaucoma and epilepsy could be available in the past at reasonable price, and now be prohibitively expensive.

    ----

    I keep thinking that some patients now considered to have ME/CFS/SEID must have been given CA inhibitors in the past. I've been the subject of a long list of uncontrolled experiments, and I wonder why nobody ever considered one of the disorders treated with CA inhibitors. There was certainly speculation about epilepsy with "silent seizures", though my EEGs came back clear of problems.

    I'll reiterate my general request to readers. Look over that list of carbonic anhydride inhibitors above, and if you recognize any drugs you have been given, tell us about your experiences.
     
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  5. xrayspex

    xrayspex Senior Member

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    I was just doing a search about Diamox and this class of meds because I suspect I am verging on intracranial hypertension (ICH) headaches. I have gone thru periods over the last 15 years where i suspected it. It usually happens in response to a medication or treatment. IE opiates, ritalin, zantac, and prilosec in the past--did strange things to my heart/blood pressure where I would get awful headache only when in horizontal position usually where would want to pull hair out the pressure was so bad. And of course with CFS/ME I wanted to lie down a lot so was bit of quandry. I havent had many symptoms of it for like 5 years because let go looking to meds for the answers since they usually cause more trouble than worth for me. I did consider trying something like diamox during the worst of it but never took action because I am prone to side effects and it doesn't necessarily sound like an easily metabolized drug.

    But I am thinking about carbonic anhydrase inhibitors again because been getting racing heart at times when waking up in morning or trying to go to sleep at night and at night been getting some of those headaches again, not quite as bad as years back but not good either. I am pretty sure its being triggered by trying frequency specific microcurrent (FSM) treatment. First I want to say I am really impressed with FSM as possible modality to happen chronic pain and fatigue (google it and carol mcmakin to learn more; If I get thru this and find a balance will come back and start a thread, jury still out) but unfortunately it either triggered my heart or autonomic nervous system. I think it happened when I tried a different type that gives off a tangible microcurrent (whereas most FSM, unlike TENs is imperceptible, you dont feel it). It increases ATP and I suspect that is part of the heart of it perhaps for me---maybe there is reason with whatever is wrong with me that my body doesnt want ATP or other things improved....because ironically it sometimes seems that the remedies that are the most powerful and seem to really help also then that have this sort of backlash for me.

    So anyway, I am curious like Anciendaze was if many CFS/ME have tried meds like Diamox as it seems like a worthy one to give a shot (supposed to help ICH). If there are any updates about this treatment would love to hear.

    also I have always had low b/p and did have a tilttable test in cardiology 20 years ago showing neurally mediated hypotension after admin of the med to induce it. I dont think I have had full blown pots much over the years but I wonder if certain treatments that increase heart push me into that territory.
     
    Last edited: May 19, 2017
  6. xrayspex

    xrayspex Senior Member

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    Adreno, did you have any occasion to want to try to take a carbonic anhydrase inhibitor ?
     

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